EP0485583B1 - Verwendung von tetrahydro-isoquinoline-derivate zur herstellung eines arzneimittels mit antitumoraler wirkung - Google Patents

Verwendung von tetrahydro-isoquinoline-derivate zur herstellung eines arzneimittels mit antitumoraler wirkung Download PDF

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Publication number
EP0485583B1
EP0485583B1 EP91911121A EP91911121A EP0485583B1 EP 0485583 B1 EP0485583 B1 EP 0485583B1 EP 91911121 A EP91911121 A EP 91911121A EP 91911121 A EP91911121 A EP 91911121A EP 0485583 B1 EP0485583 B1 EP 0485583B1
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Prior art keywords
product
radical
represent
hydrogen atom
methyl
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EP91911121A
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French (fr)
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EP0485583A1 (de
Inventor
Daniel Frechet
Christian Marchandeau
Jörg Czech
Hans Harald Sedlacek
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Sanofi Aventis France
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Roussel Uclaf SA
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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/475—Quinolines; Isoquinolines having an indole ring, e.g. yohimbine, reserpine, strychnine, vinblastine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • the invention relates to the use of derivatives of tetrahydro isoquinoline for the preparation of an anti-tumor medicament and in particular of an anticancer medicament, the application as medicaments of derivatives of tetrahydro isoquinoline and derivatives thereof of this structure.
  • oncogenes in a mammalian cell leads to the transformation of normal cell types into cancer cells. Said transformation is caused by the infection of a cell by a retrovirus.
  • a retrovirus We can cite as a well-known example the infection of chickens by the Rous virus which leads to the appearance of cancer.
  • the corresponding oncogene which is responsible for the malignant transformation has been called the "SRC" gene (JS Grugge RL Erikson, Nature 269 , 346-348 (1977).
  • oncogenes are characterized by the expression of a protein possessing kinase activity. These enzymes catalyze the transfer of the terminal phosphate group from ATP to an amino acid. Unlike many other proteinkinases which transfer the phosphate group to a seryl or threonyl residue, most oncogenic kinases phosphorylate a tyrosyl residue from the protein chain. Furthermore, it is known that the products of oncogenes, namely those of the oncogenes v-mos, v-mil and v-raf, have a specific serine / threonine proteinkinase activity (K. Rölling et al., Nature (London) 312 , 558-561 (1984), B. Singh et al., Journal of Virology 60 , 1149-1152 (1986).
  • Tyrosinekinase activity is an integral part of the function of certain growth factor receptors. New results show that the growth of many tumors depends on the presence of growth factors such as the Epidermal Growth Factor (EGF) "Transforming Growth Factor Alpha (TGFAlpha) or the “Platelet Derived Growth Factor (PDGF) (AS Goustin, GD Shipley, HL Moses, Cancer Research 46 , 1015-1029 (1986). As a consequence of the binding of growth factor with its receptor, the tyrosinekinase which is a proper component of the growth factor receptor, is stimulated.
  • EGF Epidermal Growth Factor
  • TGFAlpha Transforming Growth Factor Alpha
  • PDGF Platinum Derived Growth Factor
  • a tyrosinekinase and also serine / threoninekinase inhibitor can inhibit tumor growth and proliferation and can be used in anti-tumor therapy.
  • the products of formula (I) as defined below are inhibitors of oncogenic kinases such as tyrosinekinase, serine / threoninekinase and tyrosinekinase of the growth factor receptor and are therefore usable for the treatment of tumor diseases.
  • the products of formula (I) which have anti-proliferative, anti-oncotic and carcinostatic properties can in particular be used to inhibit tumor growth and proliferation and in tumor therapy.
  • the subject of the present invention is the use of the products of general formula (I): in which : X represents a hydrogen atom and Y represents a radical: in which R 'and R'1 are such that: or else they are identical and each represents a hydrogen atom or a hydroxy radical, or else they are identical or different and each represents an alkoxy radical having from 1 to 4 carbon atoms, preferably methoxy and Ar represents a radical: in which R2 and R3, which are identical or different, represent a hydrogen atom or an alkyl radical having from 1 to 4 carbon atoms, preferably methyl, and R1 represents a hydrogen atom or a methyl radical, as well as their addition salts with mineral or organic acids for the preparation of an anti-tumor medicament.
  • Products which have an asymmetric carbon can of course be in racemic or optically active form.
  • R 'and R'1 mention may be made, in addition to the hydrogen and hydroxy values, of the methoxy, ethoxy, propyloxy, isopropyloxy, butyloxy, isobutyloxy, tert-butyloxy values.
  • the addition salts with mineral or organic acids can be, for example, the salts formed with hydrochloric, hydrobromic, nitric, sulfuric, phosphoric, acetic, formic, propionic, malonic, maleic, fumaric, succinic, tartaric, citric acids. , oxalic, glyoxylic, aspartic, alkanesulfonic such as methane or ethanesulfonic acids, arenesulfonic, such as benzene or paratoluene sulfonic and arylcarboxylic acids, such as benzoic.
  • the preferred salts are the hydrochlorides, hydrobromides and acetates.
  • the medicaments which are the subject of the present invention may be in the form of pharmaceutical compositions intended for administration by the digestive, parenteral or local route. They can be prescribed in the form of simple or coated tablets, capsules, granules, suppositories, injections, ointments, creams, gels, which are prepared according to the usual methods.
  • the active ingredient (s) can be incorporated therein into excipients usually used in these pharmaceutical compositions, such as talc, gum arabic, lactose, starch, magnesium stearate, cocoa butter, aqueous vehicles or not , fatty substances of animal or vegetable origin, paraffinic derivatives, glycols, various wetting agents, dispersants or emulsifiers, preservatives.
  • excipients usually used in these pharmaceutical compositions such as talc, gum arabic, lactose, starch, magnesium stearate, cocoa butter, aqueous vehicles or not , fatty substances of animal or vegetable origin, paraffinic derivatives, glycols, various wetting agents, dispersants or emulsifiers, preservatives.
  • the dosage varies depending on the condition to be treated and the route of administration, it can vary for example from 10 to 500 mg per day in adults by oral route.
  • the usable dose can be 50 to 250 mg per day orally.
  • a subject of the invention is also, as a medicament, 3-phenylmethyl 1,2,3,4-tetrahydro isoquinoline 6,7-diol and 3 - [(3,4-dihydroxyphenyl) methyl] 1,2,3 , 4-tetrahydro isoquinoline 6,7-diol and their salts with pharmacologically acceptable mineral or organic acids.
  • a subject of the invention is also pharmaceutical compositions containing, as active ingredient, the medicament as defined above.
  • compositions which are the subject of the invention can be prepared as indicated above.
  • a subject of the invention is also 3-phenylmethyl 1,2,3,4-tetrahydro isoquinoline 6,7-diol and 3 - [(3,4-dihydroxyphenyl) methyl] 1,2,3,4-tetrahydro isoquinoline 6,7-diol and their salts with mineral or organic acids.
  • the invention therefore also relates to a process for the preparation of 3-phenylmethyl 1,2,3,4-tetrahydro isoquinoline 6,7-diol and of 3 - [(3,4-dihydroxyphenyl) methyl] 1,2,3 , 4-tetrahydro isoquinoline 6,7-diol and their salts, characterized in that a hydrolysis agent is made to act on a product of formula (II): or a salt of this product, in which the identical or different Alk1 and Alk2 represent an alkyl radical having from 1 to 4 carbon atoms and R ' a and R' 1a represent: or each one a hydrogen atom, or they are the same or different and represent each an alkoxy radical having from 1 to 4 carbon atoms, to obtain the desired product in the form of the free base and optionally salifies this product with a mineral or organic acid.
  • a hydrolysis agent is made to act on a product of formula (II): or a salt of this product, in which the
  • Alk1 and Alk2 can be chosen from the alkyl values indicated above for R1 and R3.
  • R ' a and R' 1a can be chosen from the values indicated above for R 'and R'1.
  • a product of formula (III) is reacted: in which Alk1 and Alk2 have the meaning indicated above, with a product of formula (IV) in the presence of a base such as sodium ethylate: in which R '' a and R '' 1a, which are identical or different, represent an alkoxy radical having from 1 to 4 carbon atoms, preferably methoxy and Alk3 represents an alkyl radical having from 1 to 4 carbon atoms, preferably ethyl, for obtain a product of formula (V): which is subjected to acid hydrolysis, preferably in the presence of dilute sulfuric acid to obtain a product of formula (VI): which is subjected to the action of hydroxylamine or of a hydroxylamine salt such as the hydrochloride to obtain a product of formula (VII): which is transformed, for example in the presence of sodium in ethanol, into the product of formula (VIII): which are treated with formic anhydride to obtain a product of formula (II ')
  • Aromatics 1631 - 1612 - 1582 (strong) - 1529 (strong) - 1499 cm ⁇ 1
  • EGF receptor tyrosinekinase Epidermal Growth Factor
  • Membranes of A431 cells (ATCC CRL 1555) are used as a source of EGF receptors. This cell line expresses on its surface a large number of EGF receptors which have tyrosinekinase activity.
  • HEPES N-2-hydroxyethyl-piperazine N'-2-ethanesulfonic acid
  • Mg2+ ions 10 mM
  • Mn2+ 2 mM
  • Samples containing or not containing the poly substrate (Glu, Ala, Tyr 6: 3: 1) are prepared. The reaction is initiated by the addition of [gamma32P] ATP (32 micromoles). After incubation for 15 minutes at 30 ° C, the samples are precipitated using 10% chloroacetic acid, filtered through a Millipore ® membrane and the incorporated 32P is measured with a liquid scintillation counter.
  • CI50 concentration of substance that inhibits 50% of the activity of the enzyme, determined by a series of dilutions starting at 51 micrograms / ml in the samples containing the substrate. and the EGF.

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  • Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Epidemiology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Other In-Based Heterocyclic Compounds (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)

Claims (5)

  1. Verwendung der Produkte der allgemeinen Formel (I)
    Figure imgb0022
     in der:
    X ein Wasserstoffatom darstellt und Y einen Rest
    Figure imgb0023
     bedeutet, worin R' und R'₁ sind:
    entweder sind sie gleich und stellen jeweils ein Wasserstoffatom oder einen Hydroxyrest dar,
    oder sie sind gleich oder verschieden und stellen jeweils einen Alkoxyrest mit 1 bis 4 Kohlenstoffatomen dar, vorzugsweise Methoxy, und Ar bedeutet einen Rest
    Figure imgb0024
     worin R₂ und R₃, gleich oder verschieden, ein Wasserstoffatom oder einen Alkylrest mit 1 bis 4 Kohlenstoffatomen, vorzugsweise Methyl, darstellen,
    und R₁ ist ein Wasserstoffatom oder ein Methylrest, sowie ihrer Additionssalze mit Mineralsäuren oder organischen Säuren zur Herstellung eines Arzneimittels mit antitumoraler Wirkung.
  2. Als Arzneimittel das 3-Phenylmethyl-1,2,3,4-tetrahydro-isochinolin-6,7-diol und das 3-[(3,4-Dihydroxyphenyl)-methyl]-1,2,3,4-tetrahydro-isochinolin-6,7-diol sowie ihre Salze mit pharmakologisch akzeptablen Mineralsäuren oder organischen Säuren.
  3. Pharmazeutische Zusammensetzungen, die als Wirkstoff mindestens eines der Arzneimittel nach Anspruch 2 enthalten.
  4. 3-Phenylmethyl-1,2,3,4-tetrahydro-isochinolin-6,7-diol und 3-[(3,4-Dihydroxyphenyl)-methyl]-1,2,3,4-tetrahydro-isochinolin-6,7-diol und ihre Salze mit Mineralsäuren oder organischen Säuren.
  5. Verfahren zur Herstellung des in Anspruch 4 beschriebenen Produktes und seiner Salze, dadurch gekennzeichnet, daß man ein Hydrolysierungsmittel mit einem Produkt der Formel (II)
    Figure imgb0025
     oder mit einem Salz dieses Produktes zur Reaktion bringt, worin Alk₁ und Alk₂, gleich oder verschieden, einen Alkylrest mit 1 bis 4 Kohlenstoffatomen darstellen und R'a und R'1a bedeuten:
    entweder jeweils ein Wasserstoffatom,
    oder sie sind gleich oder verschieden und stellen jeweils einen Alkoxyrest mit 1 bis 4 Kohlenstoffatomen dar,
    um das gesuchte Produkt in Form der freien Base und gegebenenfalls durch eine Mineralsäure oder organische Säure in Salz überführt zu erhalten.
EP91911121A 1990-06-08 1991-06-06 Verwendung von tetrahydro-isoquinoline-derivate zur herstellung eines arzneimittels mit antitumoraler wirkung Expired - Lifetime EP0485583B1 (de)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
FR9007137 1990-06-08
FR909007137A FR2662940B1 (fr) 1990-06-08 1990-06-08 Utilisation de derives de la tetrahydro isoquinoleine pour la preparation de medicaments anti-tumoraux, application a titre de medicaments de derives de la tetrahydro isoquinoleine et produits derives de cette structure.
PCT/FR1991/000448 WO1991018604A1 (fr) 1990-06-08 1991-06-06 Utilisation de derives de la tetrahydro isoquinoleine pour la preparation de medicaments anti-tumoraux

Publications (2)

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EP0485583A1 EP0485583A1 (de) 1992-05-20
EP0485583B1 true EP0485583B1 (de) 1994-09-07

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EP91911121A Expired - Lifetime EP0485583B1 (de) 1990-06-08 1991-06-06 Verwendung von tetrahydro-isoquinoline-derivate zur herstellung eines arzneimittels mit antitumoraler wirkung

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EP (1) EP0485583B1 (de)
JP (1) JPH05500972A (de)
DE (1) DE69103865D1 (de)
FR (1) FR2662940B1 (de)
WO (1) WO1991018604A1 (de)

Families Citing this family (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CA2458477A1 (en) * 2001-08-27 2003-03-06 Arpida Ag 3-substituted 6,7-dihydroxytetrahydroisoquinoline derivatives for use as antibacterial agents
US7767689B2 (en) * 2004-03-15 2010-08-03 Ptc Therapeutics, Inc. Carboline derivatives useful in the treatment of cancer
UA92317C2 (ru) 2004-03-15 2010-10-25 Пи-Ти-Си ТЕРАПЬЮТИКС, ИНК. Производные карболина, пригодные для ингибирования развития кровеносных сосудов
US8076352B2 (en) 2004-03-15 2011-12-13 Ptc Therapeutics, Inc. Administration of carboline derivatives useful in the treatment of cancer and other diseases
US8076353B2 (en) 2004-03-15 2011-12-13 Ptc Therapeutics, Inc. Inhibition of VEGF translation
WO2010138685A1 (en) 2009-05-27 2010-12-02 Ptc Therapeutics, Inc. Methods for treating prostate conditions
MX373926B (es) 2009-05-27 2020-07-10 Ptc Therapeutics Inc Metodos para tratar cancer y estados no neoplasicos.
CA2763479A1 (en) 2009-05-27 2010-12-02 Ptc Therapeutics, Inc. Processes for the preparation of substituted tetrahydro beta-carbolines
WO2010138652A1 (en) 2009-05-27 2010-12-02 Ptc Therapeutics, Inc. Methods for treating kaposi sarcoma
EP3664803A4 (de) 2017-08-01 2021-05-05 PTC Therapeutics, Inc. Dhodh-inhibitor zur verwendung bei der behandlung von blutkrebs

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
INDUSTRIAL&ENGINEERING CHEMISTRY RESEARCH, Vol. 28, No. 2, 1989, WASHINGTON, US, pages 221-224; C.T. GORALSKI ET COLL.: 'Isoquinoline Alkaloids. 1. An efficient preparation of d,1-laudanosoline Hydrobromide', see page 222, see the whole document *
PATENT ABSTRACTS OF JAPAN, Vol. 013, No. 399 (C-632) 5 September 1989 & JP A-01 143833 *
PATENT ABSTRACTS OF JAPAN, Vol. 013, No. 562 (C-665)(3910) 13 December 1989 &JP A-01 233221 *

Also Published As

Publication number Publication date
EP0485583A1 (de) 1992-05-20
DE69103865D1 (de) 1994-10-13
FR2662940A1 (fr) 1991-12-13
WO1991018604A1 (fr) 1991-12-12
FR2662940B1 (fr) 1994-10-14
JPH05500972A (ja) 1993-02-25

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